Tidal volume drives inflammation during mechanical ventilation for viral respiratory infection.

OBJECTIVE: Respiratory syncytial virus lower respiratory tract infection is the most frequent cause of respiratory insufficiency necessitating mechanical ventilation in infants during the winter season. Recently, we presented a new animal model to show that mechanical ventilation aggravates respiratory syncytial virus-induced pulmonary inflammation by distinct mechanisms. We now use this model to study whether low tidal volume mechanical ventilation causes less ventilator-induced lung injury in the presence of respiratory syncytial virus lower respiratory tract infection. DESIGN: Randomized controlled experimental study. SETTING: University Medical Center animal laboratory. SUBJECTS: Male BALB/c mice, 6-8 weeks old and weighing 20-28 g. INTERVENTIONS: Mice were inoculated with respiratory syncytial virus or mock virus on day 0 and ventilated on day 1 or 5 with high (12 mL/kg) or low (6 mL/kg) tidal volume for 5 hours. MEASUREMENTS AND MAIN RESULTS: Total and differential cell counts as well as cytokine concentrations were determined in bronchoalveolar lavage fluid. Compared with nonventilated respiratory syncytial virus-infected mice, high tidal volume ventilation of respiratory syncytial virus-infected mice on day 5 enhanced bronchoalveolar lavage fluid total cell count (0.35 vs 0.99 × 10e6/mL; p < 0.01), neutrophils (0.02 vs 0.17 × 10e6/mL; p < 0.01), interleukin-6 (58 vs 250 pg/mL; p < 0.01), and keratinocyte-derived chemokine (95 vs 335 pg/mL; p < 0.01) levels. In low tidal volume ventilation of respiratory syncytial virus-infected mice, no significant difference in cell counts or cytokine concentrations was observed compared with spontaneous breathing respiratory syncytial virus-infected controls on both days. CONCLUSIONS: Low tidal volume mechanical ventilation causes less ventilation-induced cellular and cytokine influx into the bronchoalveolar space during respiratory syncytial virus lower respiratory tract infection.

Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.

Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.

Mechanical ventilation drives inflammation in severe viral bronchiolitis.

INTRODUCTION: Respiratory insufficiency due to severe respiratory syncytial virus (RSV) infection is the most frequent cause of paediatric intensive care unit admission in infants during the winter season. Previous studies have shown increased levels of inflammatory mediators in airways of mechanically ventilated children compared to spontaneous breathing children with viral bronchiolitis. In this prospective observational multi-center study we aimed to investigate whether this increase was related to disease severity or caused by mechanical ventilation. MATERIALS AND METHODS: Nasopharyngeal aspirates were collected <1 hour before intubation and 24 hours later in RSV bronchiolitis patients with respiratory failure (n = 18) and non-ventilated RSV bronchiolitis controls (n = 18). Concentrations of the following cytokines were measured: interleukin (IL)-1α, IL-1ß, IL-6, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α. RESULTS: Baseline cytokine levels were comparable between ventilated and non-ventilated infants. After 24 hours of mechanical ventilation mean cytokine levels, except for MIP-1α, were elevated compared to non-ventilated infected controls: IL-1α (159 versus 4 pg/ml, p<0.01), IL-1ß (1068 versus 99 pg/ml, p<0.01), IL-6 (2343 versus 958 pg/ml, p<0.05) and MCP-1 (174 versus 26 pg/ml, p<0.05). CONCLUSIONS: Using pre- and post-intubation observations, this study suggests that endotracheal intubation and subsequent mechanical ventilation cause a robust pulmonary inflammation in infants with RSV bronchiolitis.

Decreased expression of serum and microvascular vascular endothelial growth factor receptor-2 in meningococcal sepsis*.

OBJECTIVES: To determine the skin microvessel expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels in children with meningococcal sepsis. DESIGN: Observational study. SETTING: Two tertiary academic children hospital PICUs. PATIENTS: Children with meningococcal sepsis. INTERVENTION: Skin biopsy and blood sample collection. MEASUREMENTS AND MAIN RESULTS: Determination of skin microvessel vascular endothelial growth factor receptor 2 expression in skin biopsies by immunohistochemistry and measurement of serum-soluble vascular endothelial growth factor receptor 2 by enzyme-linked immunosorbent assay. Percentage of vascular endothelial growth factor receptor 2-positive skin microvessels and the staining intensity were significantly lower in children with meningococcal sepsis (n = 10) compared to controls (7.6% ± 8.8% vs 44.6% ± 39.2%; p = 0.009 and 0.7% ± 0.7% vs 1.7% ± 1.1%; p = 0.033, respectively). In addition, circulating serum levels of soluble vascular endothelial growth factor receptor 2 were decreased in sepsis (8,148 ± 1,140 pg/mL vs 13,414 ± 2,692 pg/mL; p < 0.001). Serum-soluble vascular endothelial growth factor receptor 2 levels (n = 28) were inversely correlated with Pediatric Risk of Mortality III score (r = -0.43; p = 0.023) and more decreased in nonsurvivors compared to survivors (5,640 ± 1,940 pg/mL vs 7,378 ± 2,336 pg/mL; p = 0.037). CONCLUSIONS: Microvascular expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels are decreased in children with sepsis. Serum-soluble vascular endothelial growth factor receptor 2 levels are inversely correlated with disease severity indicated by Pediatric Risk of Mortality III score and survival. Decreased vascular endothelial growth factor receptor 2 expression may hinder natural recovery from sepsis-associated microvascular injury and the effectiveness of therapeutic strategies targeting vascular endothelial growth factor-vascular endothelial growth factor receptor 2 signaling in sepsis patients.

Dexamethasone attenuates VEGF expression and inflammation but not barrier dysfunction in a murine model of ventilator-induced lung injury.

BACKGROUND: Ventilator-induced lung injury (VILI) is characterized by vascular leakage and inflammatory responses eventually leading to pulmonary dysfunction. Vascular endothelial growth factor (VEGF) has been proposed to be involved in the pathogenesis of VILI. This study examines the inhibitory effect of dexamethasone on VEGF expression, inflammation and alveolar-capillary barrier dysfunction in an established murine model of VILI. METHODS: Healthy male C57Bl/6 mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with an inspiratory pressure of 10 cmH2O ("lower" tidal volumes of ∼7.5 ml/kg; LVT) or 18 cmH2O ("higher" tidal volumes of ∼15 ml/kg; HVT). Dexamethasone was intravenously administered at the initiation of HVT-ventilation. Non-ventilated mice served as controls. Study endpoints included VEGF and inflammatory mediator expression in lung tissue, neutrophil and protein levels in bronchoalveolar lavage fluid, PaO2 to FiO2 ratios and lung wet to dry ratios. RESULTS: Particularly HVT-ventilation led to alveolar-capillary barrier dysfunction as reflected by reduced PaO2 to FiO2 ratios, elevated alveolar protein levels and increased lung wet to dry ratios. Moreover, VILI was associated with enhanced VEGF production, inflammatory mediator expression and neutrophil infiltration. Dexamethasone treatment inhibited VEGF and pro-inflammatory response in lungs of HVT-ventilated mice, without improving alveolar-capillary permeability, gas exchange and pulmonary edema formation. CONCLUSIONS: Dexamethasone treatment completely abolishes ventilator-induced VEGF expression and inflammation. However, dexamethasone does not protect against alveolar-capillary barrier dysfunction in an established murine model of VILI.

Clinical pharmacy interventions in paediatric electronic prescriptions.

OBJECTIVE: To examine the frequency, nature and determinants of clinical pharmacy interventions in paediatric electronic prescriptions. DESIGN: Prospective cohort with nested case-control study. SETTING: Tertiary children's hospital, The Netherlands. PATIENTS: Patients 0-18 years with at least one drug prescription admitted to hospital between 1 March 2004 and 1 January 2008, excluding patients receiving intensive care. INTERVENTIONS: Electronic medication prescriptions for paediatric inpatients were verified and if necessary interventions were made by the paediatric clinical pharmacy. Prescriptions requiring intervention (cases) were compared with prescriptions not requiring interventions (controls). MAIN OUTCOME MEASURES: Frequency of clinical pharmacy interventions, per 10 000 paediatric electronic prescriptions, and the determinants thereof. RESULTS: Interventions were made for 1577 (1.1%) of 138 449 prescriptions. 81% of the interventions concerned correction of a prescription that might have had adverse clinical consequences. Interventions in prescriptions for antibacterial agents for systemic use were made most often. Most corrections concerned wrong doses (45%). 1577 cases were compared with 1983 controls. The risk of interventions was higher for children aged 1 month to 2 years than for 12-18-year-olds (OR=1.97 (95% CI 1.63 to 2.38)). The risk for 'free-text' prescriptions was five times higher than for 'standardised structured template' prescriptions. No differences were found between day, evening and night shift prescriptions. Significantly more interventions were made in the oral dosage form (OR=1.63 (95% CI 1.41 to 1.88)) and administration route (OR=1.80 (95% CI 1.55 to 2.09)) than for other reasons. CONCLUSIONS: Paediatric prescribing errors occur frequently and are not completely prevented by electronic prescribing systems. This study provides information for improvements in electronic prescribing for paediatric patients. Incorporating tailored solutions, such as minimised free-text entry, certain obligatory fields and integrated dose checking and indications, can improve the quality and efficiency of electronic prescribing in paediatrics.

Host response to mechanical ventilation for viral respiratory tract infection.

Respiratory syncytial virus (RSV) bronchiolitis causes severe respiratory tract infection in infants, frequently necessitating mechanical ventilatory support. However, life-saving, mechanical ventilation aggravates lung inflammation. We set up a model to dissect the host molecular response to mechanical ventilation in RSV infection. Furthermore, the response to induced hypercapnic acidosis, reported to dampen the inflammatory response to mechanical ventilation in non-infectious models, was assessed. BALB/c mice were inoculated with RSV or mock-suspension and ventilated for 5 h on day 5 post inoculation. Mechanical ventilation of infected mice resulted in enhanced cellular influx and increased concentrations of pro-inflammatory cytokines in the bronchoalveolar space. Microarray analysis showed that enhanced inflammation was associated with a molecular signature of a stress response to mechanical ventilation with little effect on the virus-induced innate immune response. Hypercapnic acidosis during mechanical ventilation of infected mice did not change host transcript profiles. We conclude that mechanical ventilation during RSV infection adds a robust but distinct molecular stress response to virus-induced innate immunity activation, emphasising the importance of lung-protective mechanical ventilation strategies. Induced hypercapnic acidosis has no major effect on host transcription profiles during mechanical ventilation for RSV infection, suggesting that this is a safe approach to minimise ventilator-induced lung injury.

FOXP3+ CD4+ Tregs lose suppressive potential but remain anergic during transient inflammation in human.

Tregs are crucial in controlling inflammation. Although the transcription factor FOXP3 is the most applicable phenotype marker of Tregs, it does not indisputably characterize suppressive function during T-cell activation in vitro. A question that remains is: what is the functionality of FOXP3(+) T cells during inflammation in vivo? We studied FOXP3(+) T cells in a human model of acute inflammation due to cardiac surgery. Twenty-five children who underwent cardiac surgery for correction of a septum defect were included. Following surgery, we observed a transient systemic inflammatory response accompanied by an increased proportion of CD25(bright) T cells with sustained Treg phenotype. During this transient immune activation, both the percentage of CD4(+) FOXP3(+) cells and the level of expression of FOXP3 in the CD4(+) CD25(bright) CD127(low) population increased. While Tregs remained present during systemic inflammation and continued to be anergic, the capacity to suppress effector T cells was reduced. The reduced suppressive state of Tregs could be induced in vitro by plasma obtained during the peak of inflammation after surgery. These data show that inflammation inhibits Treg function through soluble factors present in plasma. These results underscore the functional role of FOXP3(+) Tregs during inflammation in vivo.

Angiopoietin-1 treatment reduces inflammation but does not prevent ventilator-induced lung injury.

BACKGROUND: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation. METHODS: Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH2O ('low' tidal volume ∼7.5 ml/kg; LVT) or 18 cmH2O ('high' tidal volume ∼15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 µg per animal). Non-ventilated mice served as controls. RESULTS: HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1ß caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression. CONCLUSIONS: Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilation.

Off-hours admission and mortality in two pediatric intensive care units without 24-h in-house senior staff attendance.

PURPOSE: To compare risk-adjusted mortality of children non-electively admitted during off-hours with risk-adjusted mortality of children admitted during office hours to two pediatric intensive care units (PICUs) without 24-h in-house attendance of senior staff. DESIGN: Prospective observational study, performed between January 2003 and December 2007, in two PICUs without 24-h in-house attendance of senior staff, located in tertiary referral children's hospitals in the Netherlands. METHODS: Standardized mortality rates (SMRs) of patients admitted during off-hours were compared to SMRs of patients admitted during office hours using Pediatric Index of Mortality (PIM1) and Pediatric Risk of Mortality (PRISM2) scores. Office hours were defined as week days between 8:00 a.m. and 6:00 p.m., with in-house attendance of senior staff, and off-hours as week days between 6:00 p.m. and 8:00 a.m., Saturdays, Sundays and public holidays, with one resident covering the PICU and senior staff directly available on-call. RESULTS: Of 3,212 non-elective patients admitted to the PICUs, 2,122 (66%) were admitted during off-hours. SMRs calculated according to PIM1 and PRISM2 did not show a significant difference with those of patients admitted during office hours. There was no significant effect of admission time on mortality in multivariate logistic regression with odds ratios of death in off-hours of 0.95 (PIM1, 95% CI 0.71-1.27, p = 0.73) and 1.03 (PRISM2, 95% CI 0.76-1.39, p = 0.82). CONCLUSION: Off-hours admission to our PICUs without 24-h in-house attendance of senior staff was not associated with higher SMRs than admission during office hours when senior staff were available in-house.

Mechanical ventilation for respiratory failure in children with severe neurological impairment: is it futile medical treatment?

AIM: To assess outcome for children with severe neurological impairment receiving invasive mechanical ventilation for respiratory failure. METHOD: Medical charts for all such children treated in our intensive care unit (ICU) between January 2003 and July 2008 were reviewed. Outcomes were compared with those for children with moderate neurological impairment. RESULTS: Twenty-two children with severe neurological impairment were included (nine females, 13 males; median age 7y 10mo; range 4mo-17y). The median duration of mechanical ventilation was 16 days. Six children had an uneventful 1-year survival, the others required reintubation or readmission to the ICU, or died. Eleven children were still alive 1 year after discharge from the ICU. Nine patients died of respiratory failure. None of the children in the severe group died of a heart defect. Eleven children with moderate neurological impairment were included (eight females, three males; median age 1y 1mo, range 4mo-13y). Four children had an uneventful 1-year survival. Eight children were still alive 1 year after discharge from the ICU. Two of the three non-survivors died of their heart defects. INTERPRETATION: Mechanical ventilation for respiratory failure in children with severe neurological impairment is complex and associated with limited survival. However, it cannot be regarded as futile medical treatment. Further studies are urgently needed for the rational guidance of clinical decision-making.

Ventilator-induced endothelial activation and inflammation in the lung and distal organs.

INTRODUCTION: Results from clinical studies have provided evidence for the importance of leukocyte-endothelial interactions in the pathogenesis of pulmonary diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as in systemic events like sepsis and multiple organ failure (MOF). The present study was designed to investigate whether alveolar stretch due to mechanical ventilation (MV) may evoke endothelial activation and inflammation in healthy mice, not only in the lung but also in organs distal to the lung. METHODS: Healthy male C3H/HeN mice were anesthetized, tracheotomized and mechanically ventilated for either 1, 2 or 4 hours. To study the effects of alveolar stretch in vivo, we applied a MV strategy that causes overstretch of pulmonary tissue i.e. 20 cmH2O peak inspiratory pressure (PIP) and 0 cmH2O positive end expiratory pressure (PEEP). Non-ventilated, sham-operated animals served as a reference group (non-ventilated controls, NVC). RESULTS: Alveolar stretch imposed by MV did not only induce de novo synthesis of adhesion molecules in the lung but also in organs distal to the lung, like liver and kidney. No activation was observed in the brain. In addition, we demonstrated elevated cytokine and chemokine expression in pulmonary, hepatic and renal tissue after MV which was accompanied by enhanced recruitment of granulocytes to these organs. CONCLUSIONS: Our data implicate that MV causes endothelial activation and inflammation in mice without pre-existing pulmonary injury, both in the lung and distal organs.

The effect of computerized physician order entry on medication prescription errors and clinical outcome in pediatric and intensive care: a systematic review.

CONTEXT: Pediatric and intensive care patients are particularly at risk for medication errors. Computerized physician order entry systems could be effective in reducing medication errors and improving outcome. Effectiveness of computerized physician order entry systems has been shown in adult medical care. However, in critically ill patients and/or children, medication prescribing is a more complex process, and usefulness of computerized physician order entry systems has yet to be established. OBJECTIVE: To evaluate the effects of computerized physician order entry systems on medication prescription errors, adverse drug events, and mortality in inpatient pediatric care and neonatal, pediatric or adult intensive care settings. METHODS: PubMed, the Cochrane library, and Embase up to November 2007 were used as our data sources. Inclusion criteria were studies of (1) children 0 to 18 years old and/or ICU patients (including adults), (2) computerized physician order entry versus no computerized physician order entry as intervention, and (3) randomized trial or observational study design. All studies were validated, and data were analyzed. RESULTS. Twelve studies, all observational, met our inclusion criteria. Eight studies took place at an ICU: 4 were adult ICUs, and 4 were PICUs and/or NICUs. Four studies were pediatric inpatient studies. Meta-analysis showed a significant decreased risk of medication prescription errors with use of computerized physician order entry. However, there was no significant reduction in adverse drug events or mortality rates. A qualitative assessment of studies revealed the implementation process of computerized physician order entry software as a critical factor for outcome. CONCLUSIONS: Introduction of computerized physician order entry systems clearly reduces medication prescription errors; however, clinical benefit of computerized physician order entry systems in pediatric or ICU settings has not yet been demonstrated. The quality of the implementation process could be a decisive factor determining overall success or failure.

Life-threatening human herpes virus-6 infection in early childhood: presenting symptom of a primary immunodeficiency?

OBJECTIVE: To report two previously healthy children with a life-threatening course of human herpes virus type 6 (HHV-6) infection and prolonged pediatric intensive care treatment. DESIGN: Case reports. SETTING: A 16 bed pediatric intensive care unit at a tertiary care children's hospital. PATIENTS: Two children with life-threatening HHV-6 disease. INTERVENTIONS: Both children were mechanically ventilated because of respiratory failure. A detailed viral and immunologic workup was performed and treatment with antiviral medication started. MEASUREMENTS: Polymerase chain reaction assays of plasma, cerebrospinal fluid, bronchoalveolar lavage, and lung biopsies yielded HHV-6 in both patients. Immunophenotyping and lymphocyte stimulation tests with both mitogens and antigens indicated an immunodeficiency in both patients. CONCLUSION: HHV-6 infection should be considered in infants and young children with respiratory failure or meningo-encephalitis without clear causative agent or failure to respond to empirical treatment. A thorough immunologic workup and early start with antiviral therapy in any patient with a life-threatening course of HHV-6 infection is mandatory, because a severe HHV-6 infection can be the first indication of a primary immunodeficiency.

Changes in infectious disease mortality among children in the Netherlands.

In this study we examine the changes in mortality due to infectious diseases in childhood over recent decades. We analysed mortality data among children due to infectious diseases from 1969 until 2006. This study shows a steep decline of infectious disease mortality in the 1970s, followed by a relative stabilisation thereafter. This was caused by an isolated decline in infectious disease mortality in children younger than 5 years. In children over 5 years of age the infectious disease mortality remained stable during the entire study period. Analysis of mortality data of our paediatric intensive care unit (PICU) shows an increasing trend in mortality due to infections in children with underlying illnesses. Infections in childhood have remained a stable burden of mortality over recent decades.

Survival in a recent cohort of mechanically ventilated pediatric allogeneic hematopoietic stem cell transplantation recipients.

There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies.

Intensive care unit mortality trends in children after hematopoietic stem cell transplantation: a meta-regression analysis.

BACKGROUND: There is ongoing discussion whether intensive care unit mortality has decreased over time for children after hematopoietic stem cell transplantation. OBJECTIVE: To analyze intensive care unit mortality trends in children after hematopoietic stem cell transplantation. DATA SOURCES: Search of MEDLINE, EMBASE, and Cochrane databases, and a manual review of reference lists. STUDY SELECTION: Prospective and retrospective cohort studies containing intensive care unit mortality data of children after hematopoietic stem cell transplantation. DATA EXTRACTION: Mortality statistics and features associated with mortality were abstracted from studies of interest. To assess mortality over time, the median years of inclusion in original studies were included as risk factor. A multiple random-effects meta-regression analysis was conducted to assess the independent contribution of prognostic factors on mortality. DATA SYNTHESIS: Twenty-three studies were included, reporting on 1101 intensive care unit admissions. Overall intensive care unit mortality was 60% (range, 25%-91%). Once mechanical ventilation was necessary (n = 822), mean intensive care unit mortality was 71% (range, 25%-91%). Over the years, significantly fewer intensive care unit admitted patients received mechanical ventilation (p < 0.001). Univariable analysis in all intensive care unit admitted patients showed a significant decrease in mortality associated with year of inclusion. Mechanical ventilation and pulmonary disease were associated with increased mortality. In the multiple meta-regression analysis, only pulmonary disease remained significantly associated with mortality (odds ratio = 1.21, 95% confidence interval 1.01-1.46 per 10% increase in the number of patients with pulmonary disease in studies). The association between year of inclusion and intensive care unit mortality was less pronounced (odds ratio = 0.92, 95% confidence interval 0.84-1.01). CONCLUSION: There is a widely held impression that intensive care unit mortality clearly decreased in children after hematopoietic stem cell transplantation. However, characteristics of intensive care unit admitted patients significantly changed over time. After correcting for this, an improvement in intensive care unit survival was less evident. More studies are needed before a true improvement in intensive care unit survival can be confirmed.

Improving outcome in meningococcal disease: don't forget compartment syndrome!

OBJECTIVE: To advocate a surgical intervention that can prevent the loss of limbs in patients with meningococcal disease. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A 4-month-old male infant presenting with acute circulatory failure due to meningococcal disease. INTERVENTIONS: Measurements of compartment pressures of all extremities and echo-Doppler of peripheral arteries were performed at regular intervals, starting at admittance to the pediatric intensive care unit. After compartment syndrome in the lower extremities was diagnosed, emergency surgical intervention (fasciotomy and arteriolysis) was performed in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: During surgery, the compartments initially revealed pale, poorly perfused tissue. After decompression, immediate bulging of the muscles and restoration of microcirculation were seen. All digits were spared, and muscle compartments remained vital with exception of the tibialis anterior and extensor hallucis longus muscles in the left leg. Several ecchymoses and purpura of the lower extremities caused skin necrosis, necessitating skin transplants. No other surgical intervention was required. CONCLUSIONS: In meningococcal disease, compartment syndrome can occur within hours after initial presentation due to massive capillary leakage and circulatory failure. Immediate surgical intervention is the gold standard in treatment, making early recognition vital. In all patients presenting with meningococcal disease, compartment syndrome should be considered and early monitoring included in the initial evaluation.